Tamper Resistant Pharmaceutical Formulations

ABSTRACT

Disclosed in certain embodiments is a solid oral dosage form comprising a heat-labile gelling agent; a thermal stabilizer; and a drug susceptible to abuse.

FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutical dosageforms that are resistant to tampering and abuse.

BACKGROUND

Pharmaceutical products are sometimes the subject of abuse. For example,a particular dose of opioid agonist may be more potent when administeredparenterally as compared to the same dose administered orally. Someformulations can be tampered with to provide the opioid agonistcontained therein for illicit use. Opioid agonist formulations intendedfor oral use are sometimes crushed or subject to extraction withsolvents (e.g., ethanol) by drug abusers to provide the opioid containedtherein for non-prescribed illicit use (e.g., nasal or parenteraladministration).

Controlled release oral dosage forms are sought out by abusers as thecrushing of the dosage form may liberate an amount of active agentotherwise intended for prolonged release (e.g., 12 to 24 hours), makingit immediately available. The immediate availability upon crushing mayalso make controlled release dosage forms more dangerous due to thepossibility of accidental overdose.

Immediate release oral dosage forms are also the subject of abuse. Forexample, an oral dosage form may be crushed in order to make the drugtherein available for administration by an unintended route, e.g.,parenterally or nasally.

There have previously been attempts in the art to control the abusepotential associated with opioid analgesics. For example, thecombination of pentazocine and naloxone has been utilized in tabletsavailable in the United States, commercially available as Talwin® Nxfrom Sanofi-Winthrop. Talwin® Nx contains pentazocine hydrochlorideequivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mgbase. Talwin® Nx is indicated for the relief of moderate to severe pain.The amount of naloxone present in this combination has low activity whentaken orally, and minimally interferes with the pharmacologic action ofpentazocine. However, this amount of naloxone given parenterally hasprofound antagonistic action to narcotic analgesics. Thus, the inclusionof naloxone is intended to curb a form of misuse of oral pentazocinewhich occurs when the dosage form is solubilized and injected.Therefore, this dosage has lower potential for parenteral misuse thanprevious oral pentazocine formulations. A fixed combination therapycomprising tilidine (50 mg) and naloxone (4 mg) has been available inGermany for the management of severe pain since 1978 (Valoron® N,Goedecke). The rationale for the combination of these drugs is effectivepain relief and the prevention of tilidine addiction throughnaloxone-induced antagonisms at the morphine receptor. A fixedcombination of buprenorphine and naloxone was introduced in 1991 in NewZealand (Temgesic® Nx, Reckitt & Colman) for the treatment of pain.

Commonly owned U.S. Patent Application Publication No. 20090081290 isdirected to opioid formulations that are resistant to crushing inattempts to liberate the drug contained therein for illicit use.

Commonly owned U.S. Patent Application Publication No. 20030068375 isdirected to opioid formulations that in certain embodiments include agelling agent in an effective amount to impart a viscosity unsuitablefor administration selected from the group consisting of parenteral andnasal administration to a solubilized mixture formed when the dosageform is crushed and mixed with from about 0.5 to about 10 ml of anaqueous liquid.

There exists a need in the art for a dosage form containing a drugsusceptible to abuse that is resistant to oral, parenteral and nasalabuse. In the case of opioid analgesics, there exists a need for atamper resistant formulation that does not solely rely upon theinclusion of an antagonist in the formulation to deter abuse.

All references described herein are hereby incorporated by reference intheir entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is tamper-resistant.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less oral abuse thanother dosage forms.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less parenteral abusethan other dosage forms.

It is an object of certain embodiments of the present invention toprovide a solid oral dosage form comprising a drug susceptible to abuse(e.g., an opioid analgesic), which is subject to less intranasal abusethan other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a solid oral dosage form comprising a drug susceptible toabuse (e.g., an opioid analgesic), which is subject to less diversionthan other dosage forms.

It is a further object of certain embodiments of the present inventionto provide a method of treating pain in human patients with a solid oraldosage form comprising an opioid analgesic while reducing the abusepotential of the dosage form.

It is a further object of certain embodiments of the present inventionto provide a solid oral dosage form comprising a drug susceptible toabuse (e.g., an opioid analgesic), which is resistant to dose dumping inthe presence of alcohol.

It is another object of certain embodiments of the present invention totreat a disease or condition (e.g., pain) by administering a solid oraldosage form as disclosed herein to a patient in need thereof.

It is another object of certain embodiments of the present invention toprovide a method of manufacturing an oral dosage form of a drugsusceptible to abuse (e.g., an opioid analgesic) as disclosed herein.

It is another object of certain embodiments of the present invention toprovide a use of a medicament (e.g., an opioid analgesic) in themanufacture of a tamper-resistant dosage form as disclosed herein forthe treatment of a disease state (e.g., pain).

The above objects of the present invention and others may be achieved bythe present invention which in certain embodiments is directed to asolid oral dosage form comprising a heat-labile gelling agent; a thermalstabilizer; and a drug susceptible to abuse.

In other embodiments, the invention is directed to a solid oral dosageform comprising a heat-labile gelling agent; a thermal stabilizer; apH-modifying agent and a drug susceptible to abuse.

In further embodiments, the invention is directed to a solid oral dosageform comprising a pH-sensitive gelling agent; a pH-modifying agent; anda drug susceptible to abuse.

In other embodiments, the invention is directed to a method of preparingthe solid oral dosage forms disclosed herein, e.g., in tablet or capsuleform.

In further embodiments, the present invention is directed to a method oftreating a disease or condition (e.g., pain, diarrhea or constipation)comprising administering to a patient in need thereof an oral dosageform as disclosed herein.

In describing the present invention, the following terms are to be usedas indicated below. As used herein, the singular forms “a,” “an,” and“the” include plural references unless the context clearly indicatesotherwise. Thus, for example, reference to “a drug susceptible to abuse”includes a single active agent as well as a mixture of two or moredifferent active agents, and reference to a “gelling agent” includes asingle gelling agent as well as a mixture of two or more differentgelling agents, and the like.

As used herein, the terms “active agent,” “active ingredient,”“pharmaceutical agent,” and “drug” refer to any material that isintended to produce a therapeutic, prophylactic, or other intendedeffect, whether or not approved by a government agency for that purpose.These terms with respect to specific agents include all pharmaceuticallyactive agents, all pharmaceutically acceptable salts thereof, and allcomplexes, stereoisomers, crystalline forms, cocrystals, ether, esters,hydrates and solvates thereof, and mixtures thereof, which produce theintended effect.

As used herein, the terms “therapeutically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired therapeutic result.

As used herein, the terms “prophylactically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired prophylactic result.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith one or more chiral centers that are not mirror images of oneanother (diastereomers).

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its mirror image and hence optically active whereinthe enantiomer rotates the plane of polarized light in one direction bya certain degree, and its mirror image rotates the plane of polarizedlight by the same degree but in the opposite direction.

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “patient” means a subject who has presented a clinicalmanifestation of a particular symptom or symptoms suggesting the needfor treatment, who is treated preventatively or prophylactically for acondition, or who has been diagnosed with a condition to be treated.

“Pharmaceutically acceptable salts” include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate and the like;amino acid salts such as arginate, asparaginate, glutamate and the like;metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; and organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,discyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

The term “subject” is inclusive of the definition of the term “patient”and does not exclude individuals who are entirely normal in all respectsor with respect to a particular condition.

The term “ppm” as used herein means “parts per million”. Regarding14-hydroxycodeinone, “ppm” means parts per million of14-hydroxycodeinone in a particular sample product. The14-hydroxycodeinone level can be determined by any method known in theart, preferably by HPLC analysis using UV detection.

The term “heat-labile gelling agent” means a compound or compositionthat is capable of forming a viscous solution when combined with anaqueous liquid, but which viscosity is decreased when the viscoussolution is subjected to heat.

The term “thermal stabilizer” means a compound or composition thatserves to minimize or reduce the loss of viscosity that would otherwiseoccur when a solution of a heat-labile gelling agent is subjected toheat.

The term “pH-sensitive gelling agent” means an agent that is capable offorming a viscous solution when combined with an aqueous liquid, whichviscosity is enhanced within a particular pH range.

The term “pH-modifying agent” means an agent that changes or maintains apH within a particular pH range in an environment of use (e.g., aviscous solution obtained upon tampering of the dosage form with aliquid solvent).

The term “recovery” means the amount of drug obtained from the resultantsolution of a tampered dosage form (e.g., crushing and mixing in 5 mLsolvent) upon aspiration with a 27 gauge needle.

The term “tampering” means a manipulation by mechanical, thermal, and/orchemical means to obtain a solution of drug available for illicit use.The tampering can be, e.g., by means of crushing and mixing then dosageform with a solvent (with or without heat), or by dissolution of anintact dosage form in a solvent (with or without heat).

DETAILED DESCRIPTION

Immediate and controlled release dosage forms play a vital part in themanagement of both acute and chronic conditions (e.g., pain managementwith opioid analgesics). Therefore, it is important to provide atamper-resistant dosage form of a drug susceptible to abuse that may beutilized for either controlled or immediate release to obtain a viableproduct that can provide effective plasma levels to a patient accordingto an intended release profile.

The use of gelling agents has been contemplated in order to deter theabuse of dosage forms containing a drug susceptible to abuse (e.g., anopioid analgesic). One form of abuse is via the crushing of a dosageform in order to liberate the drug contained therein for illicit usesuch as parenteral administration or through absorption across anexternal mucosal surface. When the crushed dosage form is mixed with asolution, a viscosity is obtained which inhibits the drug from beingdrawn into a needle, thereby hindering parenteral abuse. Similarly, whenthe crushed dosage form is applied to a mucosal surface (e.g., the nasalcavity), the composition forms a gel upon contact with mucosal moisture,thereby inhibiting absorption.

In order to increase the solubilization of the drug susceptible to abuse(e.g., an opioid analgesic), an abuser may heat a dosage form in anaqueous solution. This may increase the abuse potential for certaindosage forms containing gelling agents as the viscosity attained from asolubilized mixture of the dosage form may be reduced with the additionof heat, potentially facilitating parenteral or nasal administration.

Other gelling agents provide an enhanced viscosity upon solubilizationwhen they are maintained within a particular pH range. Therefore,solubilization of these formulations outside of the particular pH rangemay reduce the resultant viscosity when the dosage form is solubilized.

In certain embodiments, the present invention is directed to a solidoral dosage form comprising a heat-labile gelling agent; a thermalstabilizer; a drug susceptible to abuse; and optionally a pH-modifyingagent.

In other embodiments, the present invention is directed to a solid oraldosage form comprising a pH-sensitive gelling agent; a pH-modifyingagent; and a drug susceptible to abuse.

In certain embodiments, the heat-labile gelling agent is a polymer suchas a polysaccharide. In a particular embodiment, the polysaccharide is amicrobial polysaccharide such as xanthan gum. Xanthan gum iscommercially available from CP Kelco under the tradename Xantural®.

In embodiments of the present invention with xantham gum, agalactomannan (e.g., guar gum or locust bean gum) can be included toenhance the viscosity of the dosage form upon tampering with a solvent.

In other embodiments, the heat-labile gelling agent is a cellulosicmaterial such as hydroxypropylmethylcellulose.

In certain embodiments, the thermal stabilizer can be an additionalgelling agent different than the heat-labile gelling agent. In a certainembodiment, the thermal stabilizer is a pH-sensitive gelling agent. In aparticular embodiment, the thermal stabilizer is a polymer, e.g., apolymer that is anionic in a neutral pH aqueous solution. In aparticular embodiment, the anionic polymer is a polyacrylic acid. Thepolyacrylic acid can be a homopolymer, and can be optionally crosslinkedwith a cross-linking agent. The cross-linking agent can be a polyalcoholallyl ether such as an allyl ether pentaerythritol, an allyl ether ofsucrose, an allyl ether of propylene, or a mixture thereof. Crosslinkedhomopolymers of acrylic acid are referred to as carbomer homopolymer andcommercially available from Lubrizol under the tradename Carbopol® 71G.

In a preferred embodiment, the heat-labile gelling agent is xanthan gumand the thermal stabilizer is carbomer homopolymer.

The pH-sensitive gelling agent can also be a polymer, e.g., a polymerthat is anionic in a neutral pH aqueous solution. In a particularembodiment, the pH-sensitive gelling agent is a polyacrylic acid. Thepolyacrylic acid can be a homopolymer and can be optionally cross-linkedwith a cross-linking agent (i.e, carbomer homopolymer). Thecross-linking agent can be a polyalcohol allyl ether such as an allylether pentaerythritol, an allyl ether of sucrose, an allyl ether ofpropylene or a mixture thereof.

The pH-modifying agent can buffer the pH of a viscous solution obtainedupon tampering of the dosage form so that it is changed to, ormaintained, e.g., between about 5.5 and 8.5, between about 6 and 8, orbetween about 6.5 and 7.5. In certain embodiments, the pH-modifyingagent can be an alkaline buffer selected from the group consisting ofpotassium phosphate monobasic, sodium carbonate, sodium bicarbonate,sodium chloride, sodium phosphate dibasic and sodium phosphate monobasicsodium bicarbonate. In a particular embodiment, the pH-modifying agentis sodium bicarbonate.

In a preferred embodiment, the pH-sensitive gelling agent is carbomerhomopolymer and the pH-modifying agent is sodium bicarbonate.

The dosage forms of the present invention can include additionalexcipients in order to, e.g., aid manufacturing, provide additionaltamper resistance, modify the release rate, or provide alcoholresistance.

Additional excipients may include at least one excipient selected fromthe group consisting of bulking agents or fillers, plasticizers,stabilizers, diluents, lubricants, disintegrants, binders, granulatingaids, colorants, flavorants, and glidants.

In certain embodiments, dosage form includes a polymer that can modifythe release rate of the drug contained therein. Examples of polymersthat can be utilized to modify the release rate of the drug includepharmaceutically acceptable cellulosic polymers, including but notlimited to cellulose esters, cellulose diesters, cellulose triesters,cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulosediacylates, cellulose triacylates, cellulose acetates, cellulosediacetates, cellulose triacetates, cellulose acetate propionates,cellulose acetate butyrates and mixtures thereof. Preferably, thecellulosic polymer is an alkyl cellulosic polymer such asmethylcellulose or ethylcellulose.

Other release rate-modifying polymer include pharmaceutically acceptableacrylic polymers selected without limitation from acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride),glycidyl methacrylate copolymers, and mixtures of any of the foregoing.Preferably, the acrylic polymer is a neutral acrylic polymer (e.g.,Eudragit NE 30 D®, Eudragit NE 40 D® or Eudragit NM 30 D®), which mayalso provide crush-resistant characteristics to the dosage form.

The drug susceptible to abuse can be dry-blended with the gellingagent(s) and any additional excipients (e.g., neutral acrylic polymer)prior to being compressed incorporation into a solid oral dosage form.In other embodiments, the materials can be wet-granulated, dried, andoptionally milled prior to being incorporated into a solid oral dosageform.

In certain embodiments, a portion or all of one or more of the drug,gelling agent and any additional excipients (e.g., neutral acrylicpolymer) can be incorporated extra-granularly. For example, the drug andthe gelling agent(s) can be wet-granulated, dried and optionally milled.Thereafter, neutral acrylic polymer can be blended with the resultantgranulation to obtain the drug-containing mixture to be compressed.Materials such as glidants and lubricants can also be addedextra-granularly in order to aid in manufacturing.

A release rate-modifying polymer can be coated onto the outside of thesolid oral dosage form alternatively or in addition to inclusion of thepolymer within. The coating can include one or more of the release-ratemodifying polymers as discussed above in an amount layered over thesolid dosage form to achieve a weight gain, e.g., of from about 1% toabout 30%, from about 2% to about 15%, or from about 8% to about 12%(w/w).

Individual dosage forms can also include a film coating to enhancecosmetic appearance and/or to reduce tackiness. Examples of materials tobe utilized as a film coat include hydroxypropylmethylcellulose,polyvinyl alcohol, lactose, and mixtures thereof. The film coat can be:(i) an outer coating directly coated onto a dosage form (e.g., acompressed core), (ii) an outer coating directly coated onto acompressed core previously coated with a release rate-modifying coating,(iii) an intermediate layer between a compressed core and a release-ratemodifying coating or (iv) a unitary coating mixed with a releaserate-modifying material.

In certain embodiments, the dosage forms of the oral dosage forms of thepresent invention comprise from about 0.5% (w/w) to about 80% (w/w)neutral acrylic polymer, or from about 1% (w/w) to about 60% (w/w)neutral acrylic polymer, or from about 5% (wlw) to about 50% (w/w)neutral acrylic polymer, or from about 10% (w/w) to about 40% (w/w)neutral acrylic polymer.

Certain embodiments of the invention comprise a disintegrant in theformulation. The disintegrant can be an agent such as, e.g.,polyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodium,or a mixture thereof.

Certain embodiments of the invention comprise a filler or diluent. Thefiller or diluent can be an agent such as, e.g., lactose, dextrose,mannitol, microcrystalline cellulose, or a mixture thereof.

In certain embodiments, the solid oral dosage form of the presentinvention comprises the heat-labile gelling agent in an amount fromabout 0.25% to about 75% (w/w) of the dosage form; from about 0.1% toabout 25% (w/w) of the dosage form; or from about 0.5% to about 5% (w/w)of the dosage form.

In certain embodiments, the solid oral dosage form of the presentinvention comprises the thermal stabilizer in an amount from about 0.25%to about 90% (w/w) of the dosage form; from about 0.5% to about 50%(w/w) of the dosage form; or from about 1% to about 10% (w/w) of thedosage form.

The ratio of the heat-labile gelling agent to the thermal stabilizer canbe, e.g., from about 1:10 to about 10:1 (w/w); from about 1:5 to about5:1 (w/w); or from about 1:1 to about 1:5 (w/w).

In certain embodiments, the solid oral dosage form of the presentinvention comprises the pH-modifying agent in an amount from about 0.1%to about 25% (w/w) of the dosage form; from about 0.5% to about 10%(w/w) of the dosage form; or from about 1% to about 5% (w/w) of thedosage form.

In certain embodiments, the solid oral dosage form of the presentinvention comprises the disintegrant in an amount from about 1% to about25% (w/w) of the dosage form; from about 4% to about 15% (w/w) of thedosage form; or from about 8% to about 12% (w/w) of the dosage form.

In certain embodiments, the solid oral dosage form of the presentinvention comprises the filler or diluent in an amount from about 5% toabout 95% (w/w) of the dosage form; from about 25% to about 85% (w/w) ofthe dosage form; or from about 50% to about 75% (w/w) of the dosageform.

The ratio of the drug to the heat-labile gelling agent can be, e.g.,from about 1:40 to about 40:1 (w/w); from about 1:20 to about 20:1(w/w); from about 1:10 to about 10:1 (w/w); from about 1:5 to about 5:1(w/w); or from about 1:3 to about 3:1 (w/w).

In addition to gelling agents, the dosage forms of the present inventioncan include other aversive agents to further deter the illicit use ofthe drug contained therein. These other aversive agents can be, e.g., anemetic, an antagonist, a bittering agent, an irritant, or a mixturethereof.

The emetic may be selected from, e.g., the group consisting of methylcephaeline, cephaeline, emetine hydrochloride, psychotrine,O-methylpsychotrine, emetamine, ipecamine, hydro-ipecamine, ipecacunhicacid and mixtures thereof. In particular embodiments, the emetic isipecac.

The antagonist may be selected from, e.g., the group consisting ofnaltrexone, naloxone, nalmefene, cyclazacine, levallorphan,pharmaceutically acceptable salts thereof, and mixtures thereof.

The bittering agent may be selected from, e.g., the group consisting offlavor oils, flavoring aromatics, oleoresins, plant extracts, leafextracts, flower extracts, fruit extracts, sucrose derivatives,chlorosucrose derivatives, quinine sulphate, denatonium benzoate andmixtures thereof. In certain embodiments, the bittering agent isspearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice,mace, oil of bitter almonds, menthol or a mixture thereof. In otherembodiments, the bittering agent extracted from a fruit is selected fromthe group consisting of lemon, orange, lime, grapefruit, and mixturesthereof. In a particular embodiment, the bittering agent is denatoniumbenzoate.

The irritant may be selected from, e.g., a surfactant, capsaicin or acapsaicin analog. The capsaicin analog can be selected from the groupconsisting of resiniferatoxin, tinyatoxin, heptanoylisobutylamide,heptanoyl guaiacylamide, an isobutylamide, a guaiacylamide,dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, andmixtures thereof.

The surfactant can be selected from the group consisting of poloxamer, asorbitan monoester, a glyceryl monooleate, sodium lauryl sulfate andmixtures thereof.

The surfactant can be included in the dosage form in an amount, e.g.,from about 1% to about 25% (w/w) of the dosage form; from about 4% toabout 15% (w/w) of the dosage form; from about 2.5% to about 10% (w/w)of the dosage form or from about 8% to about 12% (w/w) of the dosageform.

The solid oral dosage forms of the present invention when mixed withfrom about 0.5 to about 10 ml of distilled water, provides a viscositythat prevents or reduces the ability of the drug from being drawn upinto a syringe, or systemically absorbed when parenteral or nasaladministration is attempted.

In certain embodiments, the viscosity provided by the solid oral dosageform after crushing and mixing with from about 0.5 to about 10 ml ofdistilled water or prevents or reduces the ability of the drug frombeing drawn up into a syringe, or systemically absorbed when parenteralor nasal administration is attempted.

In certain embodiments, the viscosity of the solid oral dosage formafter crushing and mixing with from about 0.5 to about 10 ml ofdistilled water with heat, prevents or reduces the ability of the drugfrom being drawn up into a syringe, or systemically absorbed whenparenteral or nasal administration is attempted.

In certain embodiments, the viscosity after tampering with from about0.5 to about 10 ml of distilled water is at least about 10 cP, at leastabout 50 cP, at least about 100 cP, at least about 500 cP or at leastabout 1,000 cP.

In certain embodiments, the viscosity after tampering with from about0.5 to about 10 ml of distilled water is from about 50 cP to about 1,000cP or from about 100 cP to about 5,000 cP.

In certain embodiments, the recovery of the drug is, e.g., less thanabout 10%, less than about 8%, less than about 6%, less than about 4%,less than about 2%, less than about 1%, less than about 0.8%, less thanabout 0.6%, less than about 0.4%, or less than less than about 0.2%,based on a syringability test whereby the dosage form is mixed orcrushed and mixed with 5 mL solvent and the resultant solution isaspired with a 27 gauge needle.

The solvent utilized in the syringability test can be, e.g., tap water,distilled water, sterile saline, vinegar or 40% ethanol. Also, duringthe syringability test, the solvent (before or after mixing with thedosage form) can be subject to heat from any source such as, e.g., bythe use of a butane lighter.

In certain embodiments of the present invention, the recovery of thedrug is, e.g., less than about 10%, less than about 8%, less than about6%, less than about 4%, less than about 2%, less than about 1%, lessthan about 0.8%, less than about 0.6%, less than about 0.4%, or lessthan less than about 0.2%, based on both heated and unheatedsyringability tests, whereby the dosage form is mixed or crushed andmixed with 5 mL solvent and the resultant solution is aspired with a 27gauge needle.

In certain embodiments, the ratio of extraction from an unheatedstability test to a heated stability test is from about 1:5 to about5:1; from about 1:4 to about 4:1; from about 1:3 to about 3:1; fromabout 1:2 to about 2:1; from about 1:1.5 to about 1.5:1; from about1:1.3 to about 1.3:1 or from about 1:1.1 to about 1.1:1.

Active Agents

In certain embodiments, any of the following active agents can be usedin the solid oral dosage form of the present invention: ACE inhibitors,adenohypophoseal hormones, adrenergic neuron blocking agents,adrenocortical steroids, inhibitors of the biosynthesis ofadrenocortical steroids, alpha-adrenergic agonists, alpha-adrenergicantagonists, selective alpha-two-adrenergic agonists, analgesics,anti-pyretics, anti-inflammatory agents, androgens, local and generalanesthetics, anti-addictive agents, anti-androgens, anti-arrhythmicagents, anti-asthmatic agents, anti-cholinergic agents,anti-cholinesterase agents, anti-coagulants, anti-diabetic agents,anti-diarrheal agents, anti-diuretic, anti-emetic agents, pro-kineticagents, anti-epileptic agents, anti-estrogens, anti-fungal agents,anti-hypertensive agents, anti-microbial agents, anti-migraine agents,anti-muscarinic agents, anti-neoplastic agents, anti-parasitic agents,anti-parkinson's agents, anti-platelet agents, anti-progestins,anti-schizophrenia agents, anti-thyroid agents, anti-tussives,anti-viral agents, atypical anti-depressants, azaspirodecanediones,barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergicagonists, beta-adrenergic antagonists, selective beta-one-adrenergicantagonists, selective beta-two-adrenergic agonists, bile salts, agentsaffecting volume and composition of body fluids, butyrophenones, agentsaffecting calcification, calcium channel blockers, cardiovascular drugs,cannabinoids, catecholamines and sympathomimetic drugs, cholinergicagonists, cholinesterase reactivators, contraceptive agents,dermatological agents, diphenylbutylpiperidines, diuretics, ergotalkaloids, estrogens, ganglionic blocking agents, ganglionic stimulatingagents, hydantoins, agents for control of gastric acidity and treatmentof peptic ulcers, hematopoietic agents, histamines, histamineantagonists, hormones, 5-hydroxytryptamine antagonists, drugs for thetreatment of hyperlipoproteinemia, hypnotics, sedatives,immunosupressive agents, laxatives, methylxanthines, moncamine oxidaseinhibitors, neuromuscular blocking agents, organic nitrates, opioidagonists, opioid antagonists, pancreatic enzymes, phenothiazines,progestins, prostaglandins, agents for the treatment of psychiatricdisorders, psychotropics, retinoids, sodium channel blockers, agents forspasticity and acute muscle spasms, succinimides, testosterones,thioxanthines, thrombolytic agents, thyroid agents, tricyclicantidepressants, inhibitors of tubular transport of organic compounds,drugs affecting uterine motility, vasodilators, vitamins, and mixturesthereof.

In certain embodiments, the active agent is a drug susceptible to abuse(e.g., an opioid agonist). In such embodiments, the opioid agonist isselected from the group consisting of alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, nalbuphine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and mixtures thereof. In certain embodiments,the opioid agonist is selected from the group consisting of codeine,fentanyl, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,dihydromorphine, morphine, tramadol, oxymorphone, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

In certain embodiments, the opioid agonist is oxycodone orpharmaceutically acceptable salts thereof in an amount, e.g., of about2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg.

In certain embodiments of the present invention, wherein the activeagent is oxycodone hydrochloride, the oxycodone hydrochloride has a14-hydroxycodeinone level of less than about 25 ppm, less than about 15ppm, less than about 10 ppm, less than about 5 ppm, less than about 2ppm, less than about 1 ppm, less than about 0.5 ppm or less than about0.25 ppm.

WO 2005/097801 A1, U.S. Pat. No. 7,129,248 B2 and US 2006/0173029 A1,all of which are hereby incorporated by reference, describe a processfor preparing oxycodone hydrochloride having reduced levels of14-hydroxycodeinone.

In certain embodiments, the solid oral dosage form of the presentinvention comprises an active agent that is an opioid antagonist (withor without an opioid agonist). In such embodiments, the opioidantagonist is selected from the group consisting of amiphenazole,naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine,nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocine,pharmaceutically acceptable salts thereof and mixtures thereof.

In certain embodiments, the solid oral dosage form of the presentinvention comprises an active agent that is a non-opioid analgesic. Insuch embodiments, the non-opioid analgesic is a non-steroidalanti-inflammatory agent selected from the group consisting of aspirin,celecoxib, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam, isoxicam, pharmaceutically acceptable salts thereof andmixtures thereof.

In other embodiments, the present invention is directed to the dosageforms disclosed herein utilizing active agents such as benzodiazepines,barbiturates or amphetamines, their antagonists, or combinationsthereof.

Benzodiazepines to be used in the present invention may be selected fromalprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam,estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,oxazepam, prazepam, quazepam, temazepam, triazolam, and pharmaceuticallyacceptable salts, hydrates, and solvates and mixtures thereof.Benzodiazepine antagonists that can be used in the present inventioninclude, but are not limited to, flumazenil and pharmaceuticallyacceptable salts, hydrates, and solvates.

Barbiturates to be used in the present invention include, but are notlimited to, amobarbital, aprobarbotal, butabarbital, butalbital,methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital,secobarbital and pharmaceutically acceptable salts, hydrates, andsolvates mixtures thereof. Barbiturate antagonists that can be used inthe present invention include, but are not limited to, amphetamines andpharmaceutically acceptable salts, hydrates, and solvates.

Stimulants to be used in the present invention include, but are notlimited to, amphetamines, such as amphetamine, dextroamphetamine resincomplex, dextroamphetamine, methamphetamine, methylphenidate andpharmaceutically acceptable salts, hydrates, and solvates and mixturesthereof. Stimulant antagonists that can be used in the present inventioninclude, but are not limited to, benzodiazepines, and pharmaceuticallyacceptable salts, hydrates, and solvates as described herein.

Certain embodiments contain more than one active agent. For example, thedosage forms disclosed herein can contain both an opioid agonist and anon-opioid analgesic. In particular embodiments, the non-opioidanalgesic is acetaminophen or a non-steroidal anti-inflammatory agent(e.g., ibuprofen, aspirin or diclofenac) and the opioid agonist isoxycodone, hydrocodone or pharmaceutically acceptable salts thereof(e.g., oxycodone hydrochloride or hydrocodone bitratrate).

The solid oral dosage forms of the present invention may comprise, e.g.,from about 2.5 mg to about 10 mg oxycodone or a pharmaceuticallyacceptable salt thereof; from about 2.5 mg to about 15 mg hydrocodone ora pharmaceutically acceptable salt thereof; from about 325 mg to about650 mg acetaminophen; from about 100 mg to about 800 mg ibuprofen; orfrom about 325 mg to about 750 mg aspirin.

Specific formulations may comprise about 2.5 mg oxycodone or apharmaceutically acceptable salt thereof and about 325 mg acetaminophen;about 5 mg oxycodone or a pharmaceutically acceptable salt thereof andabout 325 mg acetaminophen; about 7.5 mg oxycodone or a pharmaceuticallyacceptable salt thereof and about 325 mg acetaminophen; about 10 mgoxycodone or a pharmaceutically acceptable salt thereof and about 325 mgacetaminophen; about 7.5 mg oxycodone or a pharmaceutically acceptablesalt thereof and about 500 mg acetaminophen; about 10 mg oxycodone or apharmaceutically acceptable salt thereof and about 650 mg acetaminophen;about 5 mg oxycodone or a pharmaceutically acceptable salt thereof andabout 500 mg acetaminophen; about 2.5 mg oxycodone or a pharmaceuticallyacceptable salt thereof and about 300 mg acetaminophen; about 5 mgoxycodone or a pharmaceutically acceptable salt thereof and about 300 mgacetaminophen; about 7.5 mg oxycodone or a pharmaceutically acceptablesalt thereof and about 300 mg acetaminophen; about 10 mg oxycodone or apharmaceutically acceptable salt thereof and about 400 mg acetaminophen;about 2.5 mg oxycodone or a pharmaceutically acceptable salt thereof andabout 400 mg acetaminophen; about 5 mg oxycodone or a pharmaceuticallyacceptable salt thereof and about 400 mg acetaminophen; or about 7.5 mgoxycodone or a pharmaceutically acceptable salt thereof and about 400 mgacetaminophen.

Other formulations may comprise about 2.5 mg oxycodone or apharmaceutically acceptable salt thereof and about 325 mg aspirin; about5 mg oxycodone or a pharmaceutically acceptable salt thereof and about325 mg aspirin; about 7.5 mg oxycodone or a pharmaceutically acceptablesalt thereof and about 325 mg aspirin; about 10 mg oxycodone or apharmaceutically acceptable salt thereof and about 325 mg aspirin; about2.5 mg oxycodone or a pharmaceutically acceptable salt thereof and about500 mg aspirin; about 5 mg oxycodone or a pharmaceutically acceptablesalt thereof and about 500 mg aspirin; about 7.5 mg oxycodone or apharmaceutically acceptable salt thereof and about 500 mg aspirin; about10 mg oxycodone or a pharmaceutically acceptable salt thereof and about500 mg aspirin In certain embodiments, the formulation comprises about4.8355 mg oxycodone or a pharmaceutically acceptable salt thereof and325 mg aspirin.

Further formulations may comprise about 5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 500 mg acetaminophen;about 10 mg hydrocodone or a pharmaceutically acceptable salt thereofand about 660 mg acetaminophen; about 7.5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 750 mg acetaminophen;about 5 mg hydrocodone or a pharmaceutically acceptable salt thereof andabout 325 mg acetaminophen; about 7.5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 325 mg acetaminophen;about 10 mg hydrocodone or a pharmaceutically acceptable salt thereofand about 325 mg acetaminophen; about 7.5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 650 mg acetaminophen;about 10 mg hydrocodone or a pharmaceutically acceptable salt thereofand about 750 mg acetaminophen; about 10 mg hydrocodone or apharmaceutically acceptable salt thereof and about 500 mg acetaminophen;about 5 mg hydrocodone or a pharmaceutically acceptable salt thereof andabout 400 mg acetaminophen; about 7.5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 400 mg acetaminophen;about 10 mg hydrocodone or a pharmaceutically acceptable salt thereofand about 400 mg acetaminophen.

Additional formulations may comprise about 2.5 mg hydrocodone or apharmaceutically acceptable salt thereof and about 200 mg ibuprofen;about 5 mg hydrocodone or a pharmaceutically acceptable salt thereof andabout 200 mg ibuprofen; about 7.5 mg hydrocodone or a pharmaceuticallyacceptable salt thereof and about 200 mg ibuprofen; or about 10 mghydrocodone or a pharmaceutically acceptable salt thereof and about 200mg ibuprofen.

Pharmacokinetic Parameters

In certain embodiments, the formulations of the present inventioncomprise an opioid agonist (e.g., oxycodone hydrochloride) and provide aTmax from about 0.5 hour to about 6 hours, or from about 1 hour to about5 hours, or from about 2 hours to about 4 hours, or from about 2 hoursto about 3 hours, or from about 1 hour to about 3 hours, or about 2.5hours.

In certain embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a Cmax of about 30 ng/mL to about 50 ng/mL, or about 35ng/mL to about 45 ng/mL, or about 38 to about 42 ng/mL based on a singledose of about 15 mg to a subject; or a mean Cmax of about 30 ng/mL toabout 50 ng/mL, or about 35 ng/mL to about 45 ng/mL, or about 38 toabout 38 ng/mL based on a single dose of about 15 mg to a population ofsubjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a Cmax of about 20 ng/mL to about 35 ng/mL, or about 22ng/mL to about 32 ng/mL, or about 25 to about 30 ng/mL based on a singledose of about 10 mg to a subject; or a mean Cmax of about 20 ng/mL toabout 35 ng/mL, or about 22 ng/mL to about 32 ng/mL, or about 25 toabout 30 ng/mL based on a single dose of about 10 mg to a population ofsubjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a Cmax of about 8 ng/mL to about 20 ng/mL, or about 10 ng/mLto about 18 ng/mL, or about 12 to about 16 ng/mL based on a single doseof about 5 mg to a subject; or a mean Cmax of about 8 ng/mL to about 20ng/mL, or about 10 ng/mL to about 18 ng/mL, or about 12 to about 16ng/mL based on a single dose of about 5 mg to a population of subjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a Cmax of about 4 ng/mL to about 12 ng/mL, or about 5 ng/mLto about 10 ng/mL, or about 6 to about 8 ng/mL based on a single dose ofabout 2.5 mg to a subject; or a mean Cmax of about 4 ng/mL to about 12ng/mL, or about 5 ng/mL to about 10 ng/mL, or about 6 to about 8 ng/mLbased on a single dose of about 2.5 mg to a population of subjects.

In certain embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a AUC_(o-t) of about 150 ng*h/mL to about 350 ng*h/mL, orabout 200 ng*h/mL to about 300 ng*h/mL, or about 225 ng*h/mL to about275 ng*h/mL based on a single dose of about 15 mg to a subject; or amean AUC_(o-t) of about 150 ng*h/mL to about 350 ng*h/mL, or about 200ng*h/mL to about 300 ng*h/mL, or about 225 ng*h/mL to about 275 ng*h/mLbased on a single dose of about 15 mg to a population of subjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a AUC_(o-t) of about 100 ng*h/mL to about 300 ng*h/mL, orabout 120 ng*h/mL to about 240 ng*h/mL, or about 150 ng*h/mL to about200 ng*h/mL based on a single dose of about 10 mg to a subject; or amean AUC_(o-t) of about 100 ng*h/mL to about 300 ng*h/mL, or about 120ng*h/mL to about 240 ng*h/mL, or about 150 ng*h/mL to about 200 ng*h/mLbased on a single dose of about 10 mg to a population of subjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide a AUC_(o-t) of about 50 ng*h/mL to about 150 ng*h/mL, orabout 60 ng*h/mL to about 120 ng*h/mL, or about 75 ng*h/mL to about 100ng*h/mL based on a single dose of about 5 mg to a subject; or a meanAUC_(o-t) of about 50 ng*h/mL to about 150 ng*h/mL, or about 60 ng*h/mLto about 120 ng*h/mL, or about 75 ng*h/mL to about 100 ng*h/mL based ona single dose of about 5 mg to a population of subjects.

In other embodiments comprising oxycodone or a pharmaceuticallyacceptable salt thereof (e.g., oxycodone hydrochloride), the formulationmay provide an AUC_(o-t) of about 20 ng*h/mL to about 100 ng*h/mL, orabout 25 ng*h/mL to about 75 ng*h/mL, or about 30 ng*h/mL to about 50ng*h/mL based on a single dose of about 2.5 mg to a subject; or a meanAUC_(o-t) of about 20 ng*h/mL to about 100 ng*h/mL, or about 25 ng*h/mLto about 75 ng*h/mL, or about 30 ng*h/mL to about 50 ng*h/mL based on asingle dose of about 2.5 mg to a population of subjects.

Release Rates

The solid oral dosage forms of the present invention can provide animmediate release of the active agent or a controlled release of theactive agent. Certain embodiments can also provide a first portion ofthe active agent for immediate release and a second portion of theactive agent for controlled release.

In certain embodiments, the solid oral dosage form of the presentinvention releases at least about 85%, at least about 90% or at leastabout 95% of the active agent within 45 minutes as measured by in-vitrodissolution in a USP Apparatus 2 (paddle) at 50 rpm in 500 ml SimulatedGastric Fluid (SGF) at 37° C.

In other embodiments, the solid oral dosage form of the presentinvention releases at least about 85%, at least about 90% or at leastabout 95% of the active agent within 60 minutes as measured by in-vitrodissolution in a USP Apparatus 2 (paddle) at 50 rpm in 500 ml SimulatedGastric Fluid (SGF) at 37° C.

In alternative embodiments, the solid oral dosage form of the presentinvention provides a dissolution release rate in-vitro of the activeagent, when measured by the USP Basket Method at 100 rpm in 700 mlSimulated Gastric Fluid (SGF) without enzymes at 37° C. of at leastabout 15% by weight of the active agent released at 1 hour andthereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at37° C., of from about 25% to about 65% by weight of the active agentreleased at 2 hours, from about 45% to about 85% by weight of the activeagent released at 4 hours, and at least about 60% by weight of theactive agent released at 8 hours.

In other embodiments, the solid oral dosage form of the presentinvention provides a dissolution release rate in-vitro of the activeagent, when measured by the USP Basket Method at 100 rpm in 700 mlSimulated Gastric Fluid (SGF) without enzymes at 37° C. for 1 hour andthereafter switching to 900 ml with Phosphate Buffer at a pH of 7.5 at37° C., of at least about 20% by weight of the active agent released at4 hours, from about 20% to about 65% by weight of the active agentreleased at 8 hours, from about 45% to about 85% by weight of the activeagent released at 12 hours, and at least about 80% by weight of theactive agent released at 24 hours.

Additional Excipients

The solid oral dosage forms of the present invention can includeadditional excipients in order to, e.g., aid manufacturing, provideadditional tamper resistance, modify the release rate, or providealcohol resistance.

The additional excipient may be at least one excipient selected from thegroup consisting of bulking agents, plasticizers, stabilizers, diluents,lubricants, binders, granulating aids, colorants, flavorants, andglidants.

In certain embodiments, the solid oral dosage form can include amaterial, e.g., a polymer that can modify the release rate of the activeagent contained therein. Examples of polymers that can be utilized tomodify the release of the active agent include pharmaceuticallyacceptable cellulosic polymers, including but not limited to celluloseesters, cellulose diesters, cellulose triesters, cellulose ethers,cellulose ester-ethers, cellulose acylates, cellulose diacylates,cellulose triacylates, cellulose acetates, cellulose diacetates,cellulose triacetates, cellulose acetate propionates, cellulose acetatebutyrates and mixtures thereof. Preferably, the cellulosic polymer is analkyl cellulosic polymer such as methylcellulose or ethylcellulose.

In other embodiments of the present invention, the release-ratemodifying polymer is a pharmaceutically acceptable acrylic polymerselected without limitation from acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid), poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methylmethacrylate, polymethacrylate, poly(methyl methacrylate), poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), glycidyl methacrylatecopolymers, and mixtures of any of the foregoing. Preferably, theacrylic polymer is a neutral acrylic polymer (e.g., Eudragit NE 30 D®,Eudragit NE 40 D® or Eudragit NM 30 D®), which can also providecrush-resistant characteristics to the dosage form.

The active agent can be dry blended with the gelling agent and the otherexcipients prior to being compressed into tablets or placed into acapsule. In other embodiments the materials can be wet granulated, driedand optionally milled prior to being compressed into tablets or placedinto a capsule.

In certain embodiments, a portion or all of one or more of the activeagent, gelling agent and additional excipient can be incorporatedextra-granularly. For example, the active agent and the gelling agentcan be wet granulated, dried and optionally milled. Thereafter, anotherexcipient (e.g., thermal stabilizer) can be blended with the resultantgranulation to obtain the active agent mixture. Materials such asglidants and lubricants can also be added extragranularly in order toaid in manufacturing.

A release rate-modifying material can also be coated onto a tablet ormultiparticulates alternatively or in addition to inclusion of thematerial in the substrate. The coating can include one or more of therelease modifying polymers as discussed above in an amount over thesubstrates to achieve a weight gain, e.g., from about 1% to about 30%,from about 2% to about 15% or from about 8% to about 12%.

Individual tablets or particles can also include a film coating toenhance cosmetic appearance and/or to reduce tackiness. Examples ofmaterials to be utilized as a film coat includehydroxypropylmethylcellulose, polyvinyl alcohol, lactose or a mixturethereof. The film coat can be (i) an outer coating, (ii) an outercoating along with a release-modifying coating, or (iii) an intermediatelayer between a substrate and a release modifying coating.

Formulations and Methods of Manufacture

The solid oral dosage forms of the present invention can be in the formof, e.g., tablets, gelcaps, capsules, caplets, granules, lozenges orbulk powders. The dosage forms of the present invention can beformulated, e.g., in a unitary form (e.g., a tablet) or amultiparticulate formulation (e.g., contained in a capsule).

When the present invention is in the form of a tablet, such tablets canbe compressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multi-layered. The solid oral dosageforms of the present invention may provide an immediate release of thecompound in the gastrointestinal tract, or alternatively may provide acontrolled and/or sustained release through or at particular points inthe gastrointestinal tract. The controlled and/or sustained release maybe provided by, e.g., a coating on the oral dosage form or by theinclusion of the active agent in a controlled and/or sustained releasematrix.

The dosage forms may optionally comprise particles containing orcomprising the active agent, wherein the particles have diameter fromabout 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2mm. Additionally, the gelling agent and/or the other excipients may beincorporated into these particles, or may be incorporated into a tabletor capsule containing these particles. In certain embodiments, theparticles are film coated with a material that permits release of theactive agent at a controlled rate in an environment of use. In otherembodiments, the dosage forms of the present invention comprise acontrolled or immediate release matrix with the active agent dispersedtherein.

A unit dose of a multiparticulate dosage form of the present inventionmay include without limitation, from about 2 to about 75 particles; fromabout 10 to about 50 particles; from about 15 to about 25 particles; orfrom about 10 to about 50 particles. In other embodiments, a unit doseof an immediate release dosage form of the present invention may includewithout limitation, from about 50 to about 500 particles; from about 75to about 350 particles; from about 100 to about 300 particles; or fromabout 150 to about 250 particles.

The particles of the present invention may have a mean diameter fromabout 0.1 mm to about 10 mm; from about 0.5 mm to about 8 mm; from about1 mm to about 6 mm; or from about 2 mm to about 4 mm.

In certain embodiments comprising a drug, a heat-labile gelling agentand a thermal stabilizer, the dosage form can be in a matrix containingthe ingredients at least partially dispersed with each other in unitaryor multiparticulate form. Alternatively, the ingredients can be inlaminar arrangement in either unitary or multiparticulate form.

In certain embodiments comprising a drug, a pH-sensitive gelling agentand a pH-modifying agent, the dosage form can be in a matrix containingthe ingredients at least partially dispersed with each other in unitaryor multiparticulate form. Alternatively, the ingredients can be inlaminar arrangement in either unitary or multiparticulate form.

For example, the active agent and one or more of the excipients can beblended (with or without granulation) and compressed into a tablet.Alternatively, a granulation can be prepared which is then incorporatedinto a capsule. In further embodiments, an inert bead can be used as asubstrate for the coating of the active agent and other excipients insingle or multiple layers and placed into a capsule.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

EXAMPLES Examples 1A-E

In Examples 1A-1E, immediate release oxycodone hydrochloride tabletswith abuse deterrent properties were prepared in accordance with Table1.

TABLE 1 Strength (label claim) mg/tablet (%) Ex. 1A Ex. 1B Ex. 1C Ex. 1DEx. 1E Component and Grade Function 5 mg 10 mg 15 mg 20 mg 30 mgOxycodone HCl, USP API 5 (1.25) 10 (2.5) 15 (3.75) 20 (5) 30 (7.5)Sodium Lauryl Sulfate, NF Irritant 40 (10) 40 (10) 40 (10) 40 (10) 40(10) Magnesium Stearate, NF Lubricant 4 (1) 4 (1) 4 (1) 4 (1) 4 (1)Xanthan Gum, NF (Xantural 75) Gelling Agent 6 (1.5) 6 (1.5) 6 (1.5) 6(1.5) 6 (1.5) Carbomer Homopolymer Type A, NF Gelling Agent 20 (5) 20(5) 20 (5) 20 (5) 20 (5) (Carbopol ® 71G NF Polymer) Sodium Bicarbonate,USP pH Neutralizer 10 (2.5) 10 (2.5) 10 (2.5) 10 (2.5) 10 (2.5)Crospovidone NF (Polyplasdone XL-10) Disintegrant 36 (9) 36 (9) 36 (9)36 (9) 36 (9) Microcrystalline Cellulose, NF (Avicel Filler 279 (69.75)274 (68.5) 269 (67.25) 264 (66.0) 254 (63.5) PH102)

Manufacturing Procedure

-   -   (i) Half of the microcrystalline cellulose was added into a        V-blender.    -   (ii) The remaining ingredients, except the magnesium stearate,        were added to the blender with the oxycodone HCl passed through        a 30 mesh screen to delump.    -   (iii) The mixture was allowed to blend for 5 minutes.    -   (iv) The magnesium stearate was added, and mixed for an        additional minute.    -   (v) The blend was discharged and compressed on a Kilian Rotary        Tablet Press using caplet shaped tooling, (0.650×0.292 inches)        to a target hardness of 7 Kp and a thickness of about 4.7 mm.

Examples 2A-D Syringability Testing Procedure

A single tablet of each of Examples 2A-E set forth in Table 2 wascrushed using a 4 oz. mortar and pestle for 1 minute. The crushed tabletwas transferred to a scintillation vial. A timer was set for 5 minutes.Using a 5 mL syringe, 5 mL of solvent was added to the scintillationvial, the timer was started, and the vial was shaken for 30 seconds.This solution was poured into a small weighing dish. A small pea-sizepiece of cotton was placed in the weighing dish with the solution, andaspiration was attempted, using a 5 mL syringe with a 27 gauge needle,until the timer signaled to stop. The aspirated solution was transferredto a 25 mL volumetric flask, which was diluted with proper mobile phaseused for analysis of oxycodone HCl.

Testing the syringability on heated samples was performed in the samemanner, except that after the solvent was added, a butane lighter wasused to heat the vial until the liquid started to bubble. Then theremainder of the procedure was followed, with attempting to aspirate for5 minutes.

TABLE 2 Ingredient Ex. 2A Ex. 2B Ex. 2C Ex. 2D Oxycodone HCl 30 mg  5 mg 5 mg 30 mg MCC 262 mg  275 mg  275 mg  250 mg  Sodium Lauryl Sulfate,40 mg 40 mg 40 mg 40 mg NF Crospovidone NF 40 mg 40 mg 40 mg 40 mgXanthan Gum, NF  6 mg  6 mg  6 mg  6 mg Carbomer Homopolymer 12 mg 20 mg20 mg 20 mg Type A, NF Sodium Bicarbonate,  6 mg 10 mg 10 mg 10 mg USP[Grade 1] Magnesium Stearate, NF  4 mg  4 mg  4 mg  4 mg

In Tables 3 and 4, the data is depicted for tablets from the examples ofTable 2 which were tested for syringability at room temperature(unheated), and heated as disclosed in the syringability procedure. Tosimulate real world situations, various solvents were used. All sampleswere tested in duplicate.

TABLE 3 Unheated Sample Results Volume Oxycodone % Ex. A, B, C AspiratedRecovered Oxycodone Solvent or D (mL) (mg) Recovered Tap Water C 0.050.0249 0.5 0.05 0.0845 1.69 D 0.05 0.2906 0.97 0 0 0 Distilled Water A0.2 2.0 6.0 0.4 2.0 8.0 Sterile Saline B 0.05 0.0262 0.5 0.2 0.0951 1.9Vinegar B 0.3 0.3222 6.4 0.3 0.2722 5.4 40% Ethanol B 0.2 0.1912 3.8 0.30.2988 6.0

TABLE 4 Heated Sample Results Volume Oxycodone % Ex. A, B, C AspiratedRecovered Oxycodone Solvent or D (mL) (mg) Recovered Tap Water C 0.050.0203 0.4 0.05 0.0097 0.2 D 0.05 0.282 0.94 0.05 0.5237 1.75 DistilledWater A 0.4 2.5 8.0 0.5 3.2 11.0 Sterile Saline B 0.05 0.0282 0.6 0.20.1145 2.29 Vinegar B 0.3 0.353 7.1 0.4 0.4155 8.31 40% Ethanol B 0.30.3619 7.2 0.3 0.2585 5.2

The above data shows that the gelling agents are effective to inhibitaspiration by small volume extraction with various solvents both at roomtemperature and after the sample is heated to boiling temperature.

1. A solid oral dosage form comprising a a heat-labile gelling agent; athermal stabilizer; and a drug susceptible to abuse.
 2. The solid oraldosage form of claim 1, wherein the heat-labile gelling agent is apolymer.
 3. The solid oral dosage form of claim 2, wherein the polymeris a polysaccharide.
 4. The solid oral dosage form of claim 3, whereinthe polysaccharide is a microbial polysaccharide.
 5. The solid oraldosage form of claim 4, wherein the microbial polysaccharide is xanthangum.
 6. The solid oral dosage form of claim 1, wherein the thermalstabilizer is a gelling agent different than the heat-labile gellingagent.
 7. The solid oral dosage form of claim 6, wherein the thermalstabilizer gelling agent is a polymer.
 8. The solid oral dosage form ofclaim 7, wherein the thermal stabilizer gelling agent polymer is ananionic polymer in a neutral pH aqueous solution.
 9. The solid oraldosage form of claim 8, wherein the anionic polymer is a polyacrylicacid.
 10. The solid oral dosage form of claim 9, wherein the polymer iscarbomer homopolymer.
 11. The solid oral dosage form of claim 10,wherein the heat-labile gelling agent is a polysaccharide.
 12. The solidoral dosage form of claim 11, wherein the polysaccharide is a microbialpolysaccharide.
 13. The solid oral dosage form of claim 1, wherein theheat-labile gelling agent is xanthan gum and the thermal stabilizer iscarbomer homopolymer.
 14. The solid oral dosage form of claim 1, furthercomprising a pH-modifying agent.
 15. The solid oral dosage form of claim14, wherein the pH-modifying agent provides a pH of between about 5.5and 8.5 to a viscous solution obtained when the dosage form is crushedand mixed with 5 mL of distilled water.
 16. The solid oral dosage formof claim 15, wherein the pH-modifying agent provides a pH of betweenabout 6 and
 8. 17. The solid oral dosage form of claim 16, wherein thepH -modifying agent provides a pH of between about 6.5 and 7.5.
 18. Thesolid oral dosage form of claim 14, wherein the pH -modifying agent issodium bicarbonate.
 19. The solid oral dosage form of claim 1, furthercomprising a disintegrant.
 20. The solid oral dosage form of claim 19,wherein the disintegrant is selected from the group consisting ofpolyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodiumand a mixture thereof.
 21. The solid oral dosage form of claim 1,further comprising a filler.
 22. The solid oral dosage form of claim 21,wherein the filler is selected from the group consisting of lactose,dextrose, mannitol, microcrystalline cellulose and a mixture thereof.23. The solid oral dosage form of claim 1, comprising the heat-labilegelling agent in an amount from about 0.25% to about 75% (w/w) of thedosage form. 24-25. (canceled)
 26. The solid oral dosage form of claim1, comprising the thermal stabilizer in an amount from about 0.25% toabout 90% (w/w) of the dosage form. 27-28. (canceled)
 29. The solid oraldosage form of claim 1, wherein the ratio of the heat-labile gellingagent to the thermal stabilizer is from about 1:10 to about 10:1 (w/w).30-31. (canceled)
 32. The solid oral dosage form of claim 14, comprisingthe pH-modifying agent in an amount from about 0.1% to about 25% (w/w)of the dosage form. 33-34. (canceled)
 35. The solid oral dosage form ofclaim 19, comprising the disintegrant in an amount from about 1% toabout 25% (w/w) of the dosage form. 36-37. (canceled)
 38. The solid oraldosage form of claim 21, comprising the filler in an amount from about5% to about 95% (w/w) of the dosage form. 39-40. (canceled)
 41. Thesolid oral dosage form of claim 1, wherein the ratio of the drug to theheat-labile gelling agent is from about 1:40 to about 40:1 (w/w). 42-45.(canceled)
 46. The solid oral dosage form of claim 1, further comprisingan aversive agent.
 47. The solid oral dosage form of claim 46, whereinthe aversive agent is selected from the group consisting of emetics,antagonists, bittering agents, irritants and mixtures thereof. 48-59.(canceled)
 60. The solid oral dosage form of claim 1, wherein the drugis selected from the group consisting of opioid agonists, tranquilizers,CNS depressants, CNS stimulants, sedative hypnotics, and mixturesthereof.
 61. The solid oral dosage form of claim 1, wherein the drug isan opioid agonist.
 62. The solid oral dosage form of claim 61, whereinthe opioid agonist is selected from the group consisting of codeine,morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone,pharmaceutically acceptable salts thereof, and mixtures thereof.
 63. Thesolid oral dosage form of claim 62, wherein the opioid agonist isoxycodone or a pharmaceutically acceptable salt thereof.
 64. The solidoral dosage form of claim 63, comprising from about 5 mg to about 30 mgoxycodone or a pharmaceutically acceptable salt thereof.
 65. The solidoral dosage form of claim 1, wherein the viscosity of the dosage formmixed with from about 0.5 to about 10 ml of distilled water prevents thedrug from being systemically absorbed, or reduces the ability of thedrug to be systemically absorbed, when administered by the parenteral ornasal route.
 66. The solid oral dosage form of claim 1, wherein theviscosity of the solid oral dosage form after crushing and mixing withfrom about 0.5 to about 10 ml of distilled water prevents the drug frombeing systemically absorbed, or reduces the ability of the drug to besystemically absorbed, when administered by the parenteral or nasalroute.
 67. The solid oral dosage form of claim 65, wherein the viscosityafter mixing with from about 0.5 to about 10 ml of distilled water is atleast about 10 cP.
 68. The solid oral dosage form of claim 65, whereinthe viscosity after mixing with from about 0.5 to about 10 ml ofdistilled water is from about 50 cP to about 1,000 cP.
 69. The solidoral dosage form of claim 65, wherein the viscosity after mixing withfrom about 0.5 to about 10 ml of distilled water is from about 100 cP toabout 5,000 cP.
 70. The solid oral dosage form of claim 1, whichprovides an immediate release of the drug.
 71. The solid oral dosageform of claim 1, which provides a controlled release of the drug. 72.The solid oral dosage form of claim 70, wherein the dosage form releasesat least about 85% of the drug within 45 minutes as measured by in-vitrodissolution in a USP Apparatus 2 (paddle) at 50 rpm in 500 ml SGF at 37°C. 73-76. (canceled)
 77. The solid oral dosage form of claim 71, whichprovides a dissolution release rate in-vitro of the drug, when measuredby the USP Basket Method at 100 rpm in 700 ml Simulated Gastric Fluid(SGF) without enzymes at 37° C. of at least about 15% by weight of thedrug released at 1 hour and thereafter switching to 900 ml withPhosphate Buffer at a pH of 7.5 at 37° C., of from about 25% to about65% by weight of the drug released at 2 hours, from about 45% to about85% by weight of the drug released at 4 hours, and at least about 60% byweight of the drug released at 8 hours. 78-87. (canceled)
 88. The solidoral dosage form of claim 1, wherein the recovery of the drug is lessthan about 10% based on a syringability test whereby the dosage form iscrushed and mixed with 5 mL solvent and the resultant solution isaspired with a 27 gauge needle. 89-134. (canceled)
 135. A solid oraldosage form comprising a a pH-sensitive gelling agent; a pH-modifyingagent; and a drug susceptible to abuse.
 136. The solid oral dosage formof claim 135, wherein the pH-sensitive gelling agent is a polymer. 137.The solid oral dosage form of claim 136, wherein the polymer is ananionic polymer in a neutral pH aqueous solution.
 138. The solid oraldosage form of claim 137, wherein the anionic polymer is a polyacrylicacid.
 139. The solid oral dosage form of claim 138, wherein thepolyacrylic acid is a homopolymer.
 140. The solid oral dosage form ofclaim 139, wherein the polyacrylic acid is crosslinked.
 141. The solidoral dosage form of claim 140, wherein the polyacrylic acid iscrosslinked with a polyalcohol allyl ether.
 142. The solid oral dosageform of claim 141, wherein the polyalcohol allyl ether is selected fromthe group consisting of an allyl ether pentaerythritol, an allyl etherof sucrose, an allyl ether of propylene or a mixture thereof.
 143. Thesolid oral dosage form of claim 135, wherein the pH-modifying agentprovides a pH of between about 5.5 and 8.5 to a viscous solutionobtained when the dosage form is crushed and mixed with 5 mL ofdistilled water.
 144. The solid oral dosage form of claim 135, whereinthe pH-modifying agent provides a pH of between about 6 and
 8. 145. Thesolid oral dosage form of claim 135, wherein the pH-modifying agentprovides a pH of between about 6.5 and 7.5.
 146. The solid oral dosageform of claim 145, wherein the pH modifying agent is sodium bicarbonate.147. A method of treating a disease or condition comprisingadministering to a patient in need thereof, a solid oral dosage formaccording to claim
 1. 148. A method of treating pain comprisingadministering to a patient in need thereof, a solid oral dosage formaccording to claim
 61. 149. A method of preparing a solid oral dosageform comprising combining a heat-labile gelling agent; a thermalstabilizer; and a drug susceptible to abuse to form a unitary ormultiparticulate dosage form.
 150. (canceled)